Osteosynthesis with nano-silver

ABSTRACT

An antibacterial coating that is composed of silver is disclosed, as well as medical tools and implants comprising such a coating, and a method and an apparatus for the production of such a coating. The medical tools or the dental or orthopaedic implant comprises a metal or metal alloy having a treated surface wherein the treated surface is at least partially converted to an oxide film by plasma electrolytic oxidation using a colloid-dispersed system and wherein the converted surface is partially covered by islands formed by colloid-dispersed silver-particles of the colloid-dispersed system. An Ag—TiO 2  coating shows excellent properties in terms of antibacterial efficacy (even against multi-resistant strains), adhesion and biocompatibility. The life-time of an implant in a human body is increased. The antibacterial coating can be used in the field of traumatology, orthopaedic, osteosynthesis and/or endoprothesis, especially where high infection risk exists.

CROSS-REFERENCE TO RELATED APPLICATIONS

U.S. patent application No. 61/183,261 and German Patent application No.10 2009 023 459.4, both filed on Jun. 2, 2009, and U.S. patentapplication Ser. No. 12/792,234, filed on Jun. 2, 2010, are allincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to a multifunctionalantibacterial coating which is composed of silver, to implants and/or tomedical tools comprising such a coating and to a method as well to anapparatus for the production of such a coating.

BACKGROUND OF THE INVENTION

It is known that silver ions strongly inhibit the growth of bacteria andother microorganisms. Silver ions destroy important cell components ofmicroorganisms, so that their vital functions do not work anymore.Silver shows a broad-spectrum antibacterial activity and is evenefficient against antibiotic-resistant strains. Moreover, silver targetsnumerous sites within the bacterial cell, thus decreasing the chance forthe bacteria to develop any kind of resistance.

With increasing resistance of most of the pathogen germs against theusually used antibiotics, silver was recently rediscovered as anantibacterial active substance. In fact, due to his disinfectantproperty, silver has long been used for hygienic and medicinal purposes.

For instance, silver compounds were major weapons against woundinfection in World War I until the advent of antibiotics. In 1884 Germanobstetrician C.S.F. Crede introduced 1% silver nitrate as an eyesolution for prevention of Gonococcal ophthalmia neonatorum, which isperhaps the first scientifically documented medical use of silver.Further, silver sulfadiazine cream was a standard antibacterialtreatment for serious burn wounds and is still widely used in burnsunits.

Currently, many silver containing products are available on the marketsuch as wound dressings, catheters and/or tumor prosthetic systems.

One known coating fabrication method bases on a vacuum coating methodwhich offers reliable protection for the surfaces of medical implantsagainst bacterial contamination. A pure silver coating is applied via aPVD (Physical Vapor Deposition) process followed by a silicon oxidecoating deposited via a PECVD (Plasma Enhanced Chemical VaporDeposition) process. The coating thickness is generally below 200 nm.

PVD and CVD processes usually require highly expensive coating systems.Further, they are also energy consuming due to the high vacuumrequirements. Furthermore, the PVD technique is a “line-of-sight”technique, which means that complex surfaces would be very hard to coathomogeneously.

Moreover, irreversible pigmentation of the skin and/or the eye, i.e.argyria or argyrosis, due to possible “excessive” silver deposition, maydevelop after prolonged exposure to silver or silver compounds.

Besides, leukopenias and neuromuscular damages could be caused byincreased silver concentrations. Allergic reactions were described inthe literature. Past coating attempts with silver salts or elementarysilver were reported to cause significant increases of silverconcentrations in the serum of the concerned patients.

Accordingly, it is an object of the present invention to provide amedical device, for instance embodied as an implant, having a coating ofadvanced properties.

Preferably such a coating should be provided as an antibacterialcoating, for instance on metallic implants.

In particular it should be possible to control or to adapt theantibacterial efficacy, for instance the leaching rate, of such acoating.

Preferably the ingrowth of human tissue and/or bone should be promotedby such a coating on an implant.

The fabrication of such a coating should be based on an easy and costreduced concept.

SUMMARY OF THE INVENTION

Accordingly, the invention proposes a method for treating a surface of amedical device, in particular a metallic medical device, preferably of anon-biodegradable material, comprising the following steps:

-   -   providing a colloid-dispersed system,    -   subjecting a medical device to the colloid-dispersed system such        that a surface of the medical device which is to be treated is        immersed in the colloid-dispersed system,    -   generating a, preferably asymmetric or symmetric or a        combination of both asymmetric and symmetric, AC voltage        difference between the medical device as a first electrode        and/or a second electrode positioned in the colloid-dispersed        system    -   to convert the immersed surface to an oxide film by plasma        electrolytic oxidation wherein the converted surface is        partially covered by islands formed by colloid-dispersed        particles of the colloid-dispersed system.

The invention also proposes a medical device comprising a, preferablynon-biodegradable, metal or metal alloy having a treated surface wherein

-   -   the treated surface is at least partially converted to an oxide        film by plasma electrolytic oxidation using a colloid-dispersed        system and wherein    -   the converted surface is partially covered by islands formed by        colloid-dispersed particles of the colloid-dispersed system.

A porous oxide film or layer is grown by the plasma electrolyticoxidation (PEO) process. By the PEO process, the metallic substrate isprovided as the first electrode, preferably as an anode, in an“electrolytic cell”. Its surface is converted into the correspondingmetal oxide under the applied electrical field. The oxide film consistsof crystalline phases, with a highly porous surface and with componentsderived from both the colloid-dispersed system and the medical device,for instance an implant, as a substrate. It is provided a synthesis of ametal-oxide-particle-nanocomposite-coatings by in situ deposition. Theparticles are applied onto the surface of the medical device whenoxidizing the medical device surface. The present invention enables theformation of a coating onto any type of shape of a medical device.

The colloid-dispersed system also can be called dispersion. It is aliquid containing dispersed particles, in particular thecolloid-dispersed-particles. The colloid-dispersed-particles have a meanaverage diameter of less than or equal to 100 nm, preferably less thanor equal to 50 nm, most preferably less than or equal to 30 nm. Theparticles are also named as nano-particles. The particles are dispersedand not dissolved in the colloid-dispersed system.

Preferably the particles are not provided as a powder having generally abroad size distribution. In a preferred embodiment the particles have anarrow size distribution with a FWHM (full width at half maximum) of ≦25nm. Such a size distribution enables the formation of uniform islandsand an improved conductivity in the dispersion.

In one preferred embodiment the particles are provided bysilver-particles (Ag-particles or Ag-nano-particles). Such a nanoSilvercoating on medical device surface, for instance an implant surfaces,shows several beneficial effects: a reduction of bacterial adhesion, andan inhibition of bacterial growth. So far, no resistance mechanism wasreported and detected against silver effect. Since silver acts more likean antiseptic than an antibiotic. Such a nanoSilver coating showsexcellent properties in terms of antibacterial efficacy (even againstmulti-resistant strains), adhesion and biocompatibility (for furtherbenefits see the detailed description of the invention). This nanoSilvercontaining layer is provided by a surface chemical conversion of theimplant induced by means of the plasma electrolytic oxidation.

As a supplement or as an alternative, the particles are provided byapatite-particles, preferably HA-particles (hydroxyapatite). The apatiteis at least one apatite selected from a group consisting ofhydroxyapatite, Si-substituted hydroxyapatite, flourapatite andcarbonated apatites. At least one Ca-atom of an apatite can be replacedby a Mg, Zn, Cu, Na, K and Sr.

Hydroxyapatite improves osteoconduction. This enables for instance astrong fixation of an implant inserted in a human or animal body. TheHA-particles according to the invention also cover HA-Si-compounds(Si-substituted hydroxyapatite). A HA-Si-compound is HA-compound inwhich at least one PO₄ ³⁻ group is replaced by a SiO₄ ³⁻ group. Such aHA-Si-compound is characterized by an enhanced bio-compatibility.

As a further supplement or as a further alternative, the particles areprovided by at least one type of particles selected from a groupconsisting of copper and zinc. This type of particles also shows anantibacterial effect.

In a further embodiment an additive, preferably a nano-sized additive,is provided in the dispersion. Accordingly, the particles comprise anadditive wherein the additive is at least one material selected from agroup consisting of metals, oxides, earth minerals and phosphates. Sometypical examples are magnesia, calcium phosphate, α-TCP(tri-calcium-phosphate), sodium water glass, potassium water glassand/or silicon. Glass water is effective in bone mineralization. Theadditive is dissolved or dispersed in the colloid-dispersed system. Itis emphasized that above mentioned additives are exemplary and notrestricted to this enumeration.

The colloid-dispersed system can be based on any kind of liquid, inparticular of low or zero conductivity. In one embodiment thecolloid-dispersed system is provided as a water-based dispersion.Preferably the dispersion means are pure water or ion-exchanged water.The used water essentially comprises no electrolytes. In a preferredembodiment intentionally no additional electrolytes are introduced inthe distilled water. The ph-value of the used water is less than orequal to 7 or the ph-value of the used water is less than or equal to7.4.

The particles as the dispersed phase of the dispersion are provided witha concentration of less than or equal to 100 mg/l, preferably less thanor equal to 20 mg/l, most preferably less than or equal to 2 mg/l. Inthe most preferred embodiment the concentration is less than or equal to2 mg/l. This value is in particular suitable for metallic particles, inparticular for Ag-particles to avoid cytotoxic effects. Moreover, thesevalues are in particular suitable for metallic particles, in particularAg-particles, to provide a sufficient conductivity in thecolloid-dispersed system.

In a preferred embodiment the conductivity in the colloid-dispersedsystem is essentially only or only provided by thecolloid-dispersed-particles themselves. This is in particular suitablefor metallic particles, as for instance Ag-particles, in particular incombination with an emulsifier. Preferably the particles, for instanceAg-nano-particles, are the only carrier or the most active carrier forthe electrical charge in the dispersion. In a preferred embodiment theparticles or metallic particles are provided by a material, forming theislands on the oxide film. One material example represents silver. As asupplement or as an alternative the metallic particles or the dispersedmetallic particles are provided by a component which is a component ofthe substrate material. For instance the particles are provided byTi-particles if the substrate (representing the medical device)comprises titanium. A contamination can be avoided. Also dissolvedmaterial, as for instance dissolved material of an immersed medicaldevice, can contribute to the conductivity in the colloid-dispersedsystem.

As an alternative or as a supplement at least one electrolyte isprovided in the colloid-dispersed system. The electrolyte is dissolvedin the colloid-dispersed system. In one embodiment the electrolytecomprises at least one material selected from a group consisting ofmetals, oxides, earth minerals and phosphates. In another embodiment theelectrolyte comprises at least one electrolyte selected from a componentof the substrate material. I.e. the electrolyte is adapted to thesubstrate material. For instance the electrolyte is provided by Ti-ionsif the substrate (representing the implant) comprises titanium. Acontamination can be avoided. It is emphasized that above mentionedelectrolytes are exemplary and not restricted to this enumeration.

In a further embodiment a gas is provided in the colloid-dispersedsystem. The gas is for instance provided by a kind of bubbling.Particularly the gas is provided such to influence the PEO and/or toparticipate in the PEO. The gas comprises at least one type of gasselected from a group consisting of N₂, Ar, Kr and Xe. The mentionednoble gases are in particular suitable to achieve an enhanceddensification of the converted layer.

The converted medical device surface, for instance the converted implantsurface, is uniformly covered with the oxide layer. Preferably theconverted surface is continuously covered with the oxide layer. Theoxide film has a thickness of 1 μl to 100 μm, preferably 10 μm to 100μm, most preferably of 20 μm to 40 μm. The oxide film is characterizedby hills and/or plateaus separated by grooves and/or channels. Such anappearance represents a typical feature of a PEO process. Such astructure results in a medical device surface or implant surface oflarge specific surface area.

As already stated in the preceding description the particles are appliedonto the surface of the medical device when oxidizing the medical devicesurface. A small fraction of the particles are also embedded in theoxide layer. The main fraction of the particles is deposited onto thesurface of the oxide layer forming the islands.

There exists no sharp interface between the oxide layer and thedeposited particle layer. The particle concentration in the surfaceconverted medical device, for instance the surface converted implant, isdecreasing, preferably continuously decreasing, with increasing depth.

The islands are provided by means of micro-arcs in the PEO process, forinstance by implantation and/or deposition and/or agglomeration of thedispersed particles. The islands are surrounded by the oxide layer. Theislands have a typical average-size of less than 300 nm. An averagethickness is in the range of 5 nm to 400 nm. Some islands also can beconnected to each other. Typically, there is essentially no or only fewporosity in the islands, in particular forming nano-areas.

However, the islands represent a non-continuous layer or film, forinstance of silver, on the oxide film. In one embodiment the medicaldevice surface is a TiO—Ag-nano-composite-coating. Accordingly, theelements or compounds Ti, TiO₂, Ag and Ago are directly “visible”respectively detectable on the surface. The treated surface has anaverage island cover amount of below or equal to 20%, preferably belowor equal to 10%.

A chemical characterization of a treated surface results in acomposition of colloid-dispersed-particles, preferably silver, of 0.5 to10 at. %, preferably 1 to 10 at. % most preferably 2 to 6 at. %.

The chemical characterization of nano-silver on titanium or on atitanium alloy results in the following composition:

Ag Ti Al V O at. % 1-10 5-40 0-5 0-2 30-70

The controlling of the covering amount of the islands can be used toadjust the “effect” of the islands. For instance the antibacterialefficacy can be adjusted. One parameter for the antibacterial efficacyrepresents the leaching rate for instance of silver ions.

In the embodiment of Ag-particles the treated surface has an Ag ionsleaching rate of less than 120 ng·cm⁻²·day⁻¹. A surface treatment withsilver respectively nanoSilver shows a very high antimicrobial efficacywith very small potential side effects. Due to the high surface onvolume ratio of nanoparticles (size preferably between 2 and 50 nm), ahigh efficiency is expected even at small doses, thus, reducing the riskof noxious effect on cells.

The AC voltage or alternating voltage is applied to the first electrodeand/or the second electrode. The AC voltage is provided with a frequencyof 0.01 Hz to 1200 Hz.

In a preferred embodiment the AC voltage is provided as an asymmetric ACvoltage. The asymmetric AC voltage difference or asymmetric AC voltagerepresents an unbalanced AC voltage. This is an alternating voltage withdifferent amplitudes to the negative and the positive components. It isemphasized that a pulsed DC voltage can be also interpreted as the ACvoltage. The negative component is provided with an amplitude rangingfrom −1200 V to −0.1 V. Preferably, the negative component is providedwith an amplitude ranging from −350 V to −0.1 V. In one embodiment, thenegative component is provided with an amplitude below −180 V or rangingfrom −350 V to −180 V. The positive component is provided with anamplitude ranging from 0.1 V to 4800 V. Preferably, the positivecomponent is provided with an amplitude ranging from 0.1 V to 1400 V. Inone embodiment, the positive component is provided with an amplitudeabove +250 V or ranging from +250 V to 1400 V. In particular thequotient of the positive amplitude divided by the negative amplitudeneeds to be adjusted. The absolute value of the quotient ranges fromlarger 1 to 4.

In another embodiment the AC voltage is provided as a symmetric ACvoltage. The negative component of the AC voltage is provided with anamplitude ranging from −2400 V to −0.1 V. Preferably, the negativecomponent is provided with an amplitude ranging from −1200 V to −0.1 V.The positive component of the AC voltage is provided with an amplituderanging from +0.1 V to +2400 V. Preferably, the positive component isprovided with an amplitude ranging from 0.1 V to 1200V.

A combination of both an asymmetric and a symmetric AC voltage is alsopossible. Such a voltage distribution is for instance suitable for astep-by-step-process or a multi-step-process for the fabrication of onecoating. In a first step an asymmetric voltage or a symmetric voltage isapplied to form the coating. In a further or second step, in particularafter an interruption, the formation of the coating is continued by theapplication of a symmetric voltage or an asymmetric voltagerespectively.

The voltage difference is provided with a magnitude which is sufficientfor carrying out PEO. The voltage is above a breakdown voltage of theoxide film growing on the surface of the implant. Preferably the maximumof the AC voltage difference is provided in the range of 0.1 V to 4800V. Most preferably the maximum of the AC voltage difference is providedin the range of 100 V to 1400 V. In dependence on the conductivity ofthe colloid-dispersed system and an optional additional electrolyte, theapplied voltage difference results to a current density of 0.00001 to500 A/dm², preferably of 0.00001 to 100 A/dm². Preferably, the appliedvoltage or voltage distribution is essentially constant or unchanged andthe current density is adjusted during the PEO process.

A deposition rate in the range of 0.01 μm/s to 1 μm/s is achieved.Accordingly, with respect to the advantageous thickness of the oxidelayer and/or the particles islands a deposition time in the range of 1 sto 1200 s, preferred 1 s to 300 s, most preferred 20 s to 260 s, isachievable.

To enable a stable dispersion, the colloid-dispersed system is providedwith a temperature of −20° C. to +150° C., preferably −20° C. to +100°C., most preferably between 0° C. to 75° C. The colloid-dispersed systemis circulated with a circulation rate of 0 to 5000 liter/min, preferably0.01 to 500 liter/min. This is for instance achieved by a mixer ormixing means or stirring means. As an optional supplement an emulsifyingagent or emulsifier is provided in the colloid-dispersed system, inparticular to avoid or to reduce an agglomeration of particles. Atypical volume of the colloid-dispersed system is in the order of 0.001liter to 500 liter, preferably 0.1 liter to 500 liter, most preferably 3to 20 liter. Such volumes support an improved electrical fielddistribution in the dispersed system.

An initial medical device surface without any polishing is sufficient toachieve a suitable uniform converted surface and a suitable stablebonding of the converted surface to the bulk material. The initialsurface describes the surface before subjecting the medical device tothe PEO process. A mechanically polishing of the initial surface issufficient to achieve enhanced properties. A cost-intensiveelectro-polishing resulting in a very smooth surface is not necessary.

The invention also proposes an apparatus for the treatment of a surfaceof a medical device, in particular a metallic medical device, by plasmaelectrolytic oxidation comprising following components:

-   -   a bath for containing a colloid-dispersed system,    -   preferably means for mixing a colloid-dispersed system in the        bath,    -   means for holding a medical device such that a surface of a        medical device which is to be treated is immersed in a        colloid-dispersed system wherein a medical device provides a        first electrode,    -   means for providing a second electrode in a colloid-dispersed        system contained in the bath,    -   a power supply unit for generating an AC voltage which is        supplied to the first electrode and/or the second electrode,    -   means for connecting the first electrode and/or the second        electrode to the power supply unit wherein    -   the means for connecting the first electrode are adapted to an        immersed medical device such that the cross section ratio ranges        from 0.1 to 10. Preferably, the cross section ratio ranges from        0.75 to 4.

The cross section ratio represents the quotient of the medical devicecross section divided by the cross section of the means for connectingthe first electrode. The adapted ratio is particularly determined in thevicinity of the interface between the medical device and the means forconnecting.

Preferably the means for connecting the first electrode are embodied toprovide an essentially uniform electric field distribution between thefirst electrode and the second electrode, in particular in the vicinityof the treated surface of the medical device.

A uniform electric field distribution between the first electrode andthe second electrode is advantageous to achieve a surface conversion ofenhanced uniformity. The inventors surprisingly discovered that theelectric field distribution between the first electrode and the secondelectrode is strongly influenced by the embodiment of the means forconnecting the first electrode. In detail, the electric fielddistribution is strongly dependent on the design and/or the dimensionsof the means for connecting the first electrode.

The required uniform electric field distribution is achieved by meansfor connecting the first electrode having an adapted reduced or anadapted increased cross section with respect to the cross section of theconnected medical device. In one embodiment the means for connecting thefirst electrode have a, preferably circular, cross section with anaverage diameter of less than or equal to 5 mm, preferably less than orequal to 1.5 mm. In a preferred embodiment the means for connecting thefirst electrode are provided as a wire. The wire is metallic. The wireis embodied to carry an electric current and is for instance embodied asa thread, a rod or a strand. The wire can be flexible or non-flexible.The means for connecting the first electrode are fixed to the medicaldevice as the first electrode. The means for connecting the firstelectrode, in particular the wire, can be fixed by welding, gluing,clamping and/or screwing. Preferably, the means for connecting the firstelectrode are provided with the same material as a connected medicaldevice. It is emphasized that the means for connecting the firstelectrode can be also provided by the means for holding the medicaldevice. I.e. the means for holding the medical device and the means forconnecting the medical device are provided by only one component. In oneembodiment the means for connecting the first electrode are at leastpartially provided with a thread.

In a further embodiment means for adapting the electrical field areprovided. For instance the means for adapting the electrical field areprovided as a component to avoid edges and therefore to avoid regions ofenhanced electrical field density. In one variant according to theinvention the means for adapting the electrical field are embodied as acap. This cap can be screwed on the thread.

In another embodiment a gas supply to the colloid-dispersed system isprovided.

The antibacterial coatings according to the invention could be used inthe field of traumatology, orthopaedic, osteosynthesis and/orendoprothesis, especially where high infection risk exists. A highnumber of currently existing implants or products could benefit fromsuch a anti-bactericidal coating.

The medical device is a medical device which is at least partiallyinserted or positioned in a human body and/or an animal body. Themedical device can be any kind of a medical device.

In one embodiment the medical device is an implant. The implant is adental implant or an orthopaedic implant. Exemplary embodiments of suchan implant according to the invention are plates, screws, nails, pins,and/or all, preferably external, fixation systems. It is emphasized thatthese applications are exemplary and not restricted to this enumeration.

In another embodiment the medical device is a medical instrument ortool. Exemplary embodiments of such a medical instrument are surgicalinstruments and/or diagnostic instruments. One example of a surgicalinstrument represents a scalpel. One example of a diagnostic instrumentrepresents an endoscope. It is emphasized that these applications areexemplary and not restricted to this enumeration.

The surface converted implants according to the invention base in apreferred embodiment on biocompatible materials but preferably not onbiodegradable materials. They are intended for long-term application,for instance for several days up to months, and/or for quasi-permanentapplication, as for instance for long term implantation of surgicalimplants and/or prothesises. However, the present invention is alsoapplicable for biodegradable materials.

The implant comprises at least one metal selected from the groupconsisting of titanium, titanium alloys, chromium alloys, cobalt alloysand stainless steel. An alloy comprises at least 50 weight-% of thenamed main element. Some typical examples for titanium alloys areTiAl6V4, TiAl6Nb7 and/or TiZr. Some typical examples for chromium alloysare CrNi and/or CrNiMo. Some typical examples for cobalt alloys are CoCrand/or CoCrMo. Some typical examples for stainless steel are types 316Land/or 304. It is emphasized that above mentioned alloys are exemplaryand not restricted to this enumeration.

In particular the apparatus according to the invention is adapted toexecute any of the method steps according to the invention. Inparticular the method according to the present invention is feasible bymeans of the apparatus according to the invention. In particular themedical device, for instance an implant, according to the invention isproducible, preferably is produced, by means of the apparatus accordingto the invention and/or with the method according to the invention. Theor a medical device, for instance embodied as an implant, comprises asurface composed of an oxide film which is partially covered withislands of an antimicrobial material, preferably silver, and/or with anapatite, preferably HA.

The invention is explained subsequently in more detail on the basis ofpreferred embodiments and with reference to the appended figures. Thefeatures of the different embodiments are able to be combined with oneanother. Identical reference numerals in the figures denote identical orsimilar parts.

BRIEF DESCRIPTION OF THE DRAWINGS

It is shown in

FIG. 1 a schematically an apparatus for the fabrication of a coatingaccording to the invention,

FIG. 1 b schematically a first embodiment of the means for electricallyconnecting the medical device,

FIG. 1 c schematically a second embodiment of the means for electricallyconnecting the medical device,

FIG. 1 d schematically a third embodiment of the means for electricallyconnecting the medical device,

FIG. 1 e schematically one embodiment of an asymmetric AC voltagedistribution

FIG. 1 f schematically one embodiment of a symmetric AC voltagedistribution and

FIGS. 2 a to 10 show results of an Ag—TiO2 coating according to theinvention.

In detail, it is shown in

FIGS. 2 a-e: images of the nanoSilver coating using Stereo LightMicroscopy (a), SEM in topography contrast mode (b-c), tilted SEM intopography contrast mode (d), a schematic cross sectional view of theconverted surface (e),

FIGS. 3 a-b: (a) an SEM image of the nanoSilver coating in chemicalcontrast mode, (b) an EDX spectra of the bright region,

FIGS. 4 a-b: XPS depth profile analysis of the nanoSilver coating,

FIG. 5 a: the method steps for the preparation of the biofilm test,

FIG. 5 b: bacteria amount found on the nanoSilver, Ag-rods and Ti-alloyrods after 12 h of incubation,

FIGS. 6 a-6 e: the method steps for the preparation of the proliferationtest (a), the interpretation of the growth curves (b-d), the achievedexperimental results (e),

FIG. 7: analytical results obtained by GF-AAS, in a pseudo-dynamicmodel,

FIG. 8: analytical results obtained by GF-AAS, in a static model,

FIGS. 9 a-9 b: Stereo Light Microscopy images of a coated rod afterbending test,

FIG. 10: SEM image of ZK20 cells on nanoSilver coating and

FIG. 11: XRD image of a converted Ti-surface with a HA coating.

Subsequently, preferred but exemplar embodiments of the invention aredescribed in more detail with regard to the figures.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 illustrates an apparatus for the fabrication of a coatingaccording to the invention. The subsequent detailed description is onlydirected to an implant as one exemplary embodiment of a medical device.For instance for the coating of long term implantation surgical implantsthe present innovative technique based on the Plasma electrolyticoxidation (PEO) has been developed. PEO is an electrochemical surfacetreatment process for generating oxide coatings on metals. As a pulsedalternating current, with a high voltage, is passed through thecolloid-dispersed system 4 or the electrolyte bath 4, a controlledplasma discharge is formed and sparks are generated on the substratesurface. This plasma discharge converts the surface of the metal into anoxide coating. The coating is in fact a chemical conversion of thesubstrate and grows both inwards and outwards from the original metalsurface. Because it is a conversion coating, rather than a depositedcoating (such as a coating formed by plasma spraying), it has excellentadhesion to the substrate metal (see FIGS. 9 a and 9 b). A wide range ofsubstrate alloys can be coated with this technique.

The dispersed system 4 is provided in a bath 5. An implant 20 as a firstelectrode 1 is provided in the dispersed system 4. In the illustratedembodiment the implant 20 is completely immersed in the liquid 4respectively the dispersed system 4. A second electrode 2 is provided asa cup also immersed or provided in the colloid-dispersed system 4. Thesecond electrode 2 “surrounds” the first electrode 1.

The temperature of the dispersed system 4 is maintained or controlled bya heat exchanger 6 and/or a pumping system 7 and/or means for mixing 8.A circulation and/or mixing of the dispersed system 4 is achieved by themeans for mixing 8. The means for mixing 8 are for instance provided byan acoustic hydrodynamic generator. As a possible and shown supplement agas supply 9, for instance for air, can be also provided to the meansfor mixing 8. The circulation of the liquid avoids an agglomeration ofthe nano-particles contained in the dispersed system 4.

In a further non-shown embodiment the second electrode 2 is provided bythe bath 5 or the container 5 itself. This is for instance suitable fora container 5 which is provided by a conductive material. In such anembodiment the bath 5 and the second electrode 2 are provided asone-piece.

In a preferred embodiment the first electrode 1 is approximatelypositioned in the center of the second electrode 2 to achieve a uniformelectrical field distribution. The design of the means for connecting 3the first electrode 1 is chosen to preserve an essential uniform oradapted electric field distribution between the first electrode 1 andthe second electrode 2. For this the cross section and/or the geometryof the means for connecting 3 the implant 20 is/are adapted to the crosssection and/or the geometry of the implant 20. FIGS. 1 b to 1 dschematically show three exemplary embodiments of the means forconnecting 3 the implant 20.

FIGS. 1 b to 1 d illustrate possible embodiments of the means forconnecting 3 each having an adapted reduced cross section with respectto the implant 20. Accordingly, the cross section ratio (representingthe quotient of the medical device cross section divided by the crosssection of the means for connecting the first electrode) is greater than1 and less than 4. The reduced cross section of the means for connecting3 is illustrated by the diameters d1 and d2 with d1<d2. The adaptedreduced cross section is particularly determined in the vicinity or thearea of the interface 35 between the implant 20 and the means forconnecting 3.

In FIG. 1 b the means for connecting 3 the first electrode 1(respectively the implant 20) are embodied as a wire 3. The wire 3 isembodied as a, preferably cylindrical, rod 3. The rod 3 is embodied bothfor enabling the electrical contact and for holding the implant 20.

FIG. 1 c illustrates the coating configuration for a nut as an implant20. Since nuts 20 are generally quite small, for instance below or equalto 1 cm, the coating of a nut 20 is quite “complicated”. The means forconnecting 3 the first electrode 1 are also embodied as a wire 3. Thewire 3 is partially embodied as a, preferably cylindrical, rod 3. Theend-section of the rod 3 is embodied with a thread 31. The nut 20 isscrewed on the thread 31. A cap 32 is applied or screwed to theend-section of the thread 31. The gaps above and below the nut 20 have asize of about 1 mm. The application of such a cap 32 enables theformation of a uniform coating also on the upper and the lower frontside of the nut 20. The cap 32 represents means for adapting theelectrical field. The rod 3 is embodied both for enabling the electricalcontact and for holding the implant 20.

In FIG. 1 d the means for connecting 3 the first electrode 1(respectively the implant 20) are embodied as well as a wire 3. The wire3 is now embodied as a strand 3. The strand 3 enables only theelectrical contact. It is fedthrough a holder 33 which is preferablynon-conductive. The holder 33 mechanically holds the implant 20.

The AC voltage is provided by the power supply 10 (see FIG. 1 a). Theapplication of an asymmetric pulsed AC voltage results in a densecoating. The positive part of the pulse enables the growing of theconverted surface. At the beginning of the oxide layer growing processthe converted surface is characterized by a dense structure. Withincreasing oxide layer coating thickness the coating is getting more andmore porous. The particles of the coating are getting more and moreloosen. These loosen particles are removed in the negative part of thepulse. Accordingly, the negative part of the pulse is a so-calledetching part. An asymmetric AC voltage is a voltage with differentamplitudes to the positive and negative components. In particular thequotient of the positive amplitude divided by the negative amplitudeneeds to be adjusted. The absolute value of the quotient ranges from >1to 4. For illustration purposes FIG. 1 e schematically shows anasymmetric AC voltage distribution for amplitudes U1 of +200 V and −50V.These voltages are for instance applied to the implant 20 as the firstelectrode 1 (see FIG. 1 a). In this embodiment the voltage of the secondelectrode 2 is for instance on ground potential. The shape isillustrated as being approximately rectangular-shaped. The shape canalso be, in particular partially, a kind of a sinus or a sinus. For someapplications also a symmetric AC voltage distribution is suitable. Oneexemplary application is the obtaining of a coating with a very highsurface roughness for improved implant-bone bonding. For illustrationpurposes FIG. 1 f schematically shows a symmetric AC voltagedistribution for amplitudes U1 of −200 V and +200V.

Nanosilver particles with a particle size of about 1 to 20 nm,preferably 15 nm, are very suitable. This leads to an enhanced specificsurface area and therefore to a high amount of dissolvable silver ions.The silver ions are responsible for the specific activity against abroad variety of bacteria, fungi and yeasts.

Silver ions inactivate critical physiological functions like cell-wallsynthesis, trans-membrane transport, nucleic acid reproduction orprotein functions. All of these actions result in a short-term death ofmicroorganisms. Because of this multiple modes of antimicrobial action,it is very improbable, that the microorganisms develop a resistance tosilver. Beyond the antimicrobial activity of the silver ions, newresearch projects show, that nanosilver in particular shows an activityagainst viruses like HIV or hepatitis.

FIGS. 2 a to 11 b show experimental results of an Ag—TiO₂ coatingaccording to the invention. The used substrate or implant material isTiAl6V4 ELI alloy. TiAl6V4 ELI alloy (Extra Low Interstitials, ISO5832-3) is a higher purity grade of TiAl6V4 alloy. This grade has loweroxygen, carbon, and iron content. It is commonly used in biomedicalapplications such as surgical instruments and orthopedic implants.

First, FIGS. 2 a to 2 d show the results of a topographicalcharacterization (according to ISO/TS 10993-19:2006). As an example ascrew having a coating according to the invention was analyzed. Thecoating surface topography has been investigated by stereo lightmicroscopy (FIG. 2 a) and scanning electron microscopy (SEM) intopography contrast mode (FIGS. 2 b to 2 d).

The images show a uniform and homogeneous coating of the surface (FIGS.2 a and 2 b). At higher magnification the characteristic features of thePEO coatings are revealed: flat elevated plateaus with some deepeningbetween them (FIG. 2 c). The average deepening is 20 μm deep (FIG. 2 d).The topographical characterization reveals a dense coating with a highspecific surface area.

FIGS. 2 c and 2 d show the typical features of a converted surface byPEO. For illustration purposes FIG. 2 e schematically shows a convertedsurface in a cross sectional view. The converted surface is continuouslycovered with the oxide layer. A typical thickness is below 25 μm. Theoxide film is characterized by hills and/or plateaus separated bygrooves and/or channels. On top of the oxide layer said islands aredeveloped forming a non-continuous layer of metallic Ag and partiallyAg0. The islands can be formed on the plateaus and in the grooves. Theislands have a typical thickness below 100 nm and a typical diameterranging from 5 nm to 200 nm.

FIGS. 3 a and 3 b show the results of a physico-chemicalcharacterization (according to ISO/TS 10993-19:2006). The SEM images inchemical contrast mode show the presence of a heavy element on thecoating surface, in particular embodied as island (bright areas on FIG.3 b). Energy-dispersive spectrometry (EDS) confirms the presence ofsilver (FIG. 3 a). Silver is homogeneously or uniformly distributed allover the coating surface. The typical silver-containing areas are muchless than 1 μm.

In FIGS. 4 a and 4 b results of a chemical characterization (accordingto ISO 10993-18:2005) are presented. The surface elemental compositionwas more precisely assessed by X-ray Photoelectron Spectroscopy (XPS)using a PHI 5500 ESCA spectrometer (monochromatic Al Kα radiation), eachvalues reported below are the mean value of three independent analyses.

Ag Ti Al V C O N Cl S at. % 3.6 14.7 1.2 0.3 30.3 47.7 1.4 0.5 0.3 wt %16.8 30.4 1.4 0.7 15.7 33.0 0.8 0.8 0.4

The coating surface is mostly composed of titanium oxide with silver andcarbon. Extremely low amount of nitrogen, chlorine and sulfur has alsobeen found as contaminants.

XPS depth profiling (sputtering with a 3 keV Ar ions beam, surface area3.8×4.2 mm) was performed on the coating to investigate its in-depthcomposition uniformity; an estimation of the thickness of the silvercontaining part of the coating was thus obtained: <100 nm.

After 2 min of sputtering the carbon content sharply decreases revealingthe presence of a small organic surface contamination (FIG. 4 a). Thiscarbon surface contamination is often found by XPS and is probably dueto the transport and the handling of the samples prior to the analysis.It's, also, after 2 min of sputtering that the highest concentration ofAg is detected (FIG. 4 b).

Afterwards a continuous decrease of the Ag concentration is observed,revealing a diffusion pattern of the silver into the oxide layer. Thisobservation is also consistent with the SEM results which indicate thatthe silver is present as small particles and not as a continuous layer.There is no sharp interface between the oxide layer and the Ag island.For instance, this is in contrast to surfaces converted to an oxide anddeposited with an Ag coating.

High resolution binding spectra were also recorded (results are notshown). The O binding spectra refer mainly to TiO₂, with a small amountof other metal oxides (mainly Al and Ag). The Ag binding spectra showsthe presence of silver oxides and metallic silver, no silver chloridewas observed.

Subsequently are shown the results for the anti-microbial efficacyassessment of the coating according to the present invention. Materialsfor osteosynthesis (for instance pins, screws etc.) require for goodbiointegration a very specific surface, which allows human tissue cellsto settle on them at the same time. This surface enables bacteria tosettle, so that they compete with the human cells for proliferation onthe surface.

The purpose of a nanoSilver-coating is the prevention of problematicbacterial growth on the surface of coated materials for osteosynthesis.One task of the invention is to find an optimal silver concentration forthe coating, which shows a high antibacterial activity without anycytotoxic effect (according to ISO 10993-5).

The bacteria strain was used for every test: Staphylococcus epidermidisATCC 35984.

This bacteria strain has the following characteristics:

-   -   Primary occupant of the skin.    -   Colonizes surfaces of prosthetic devices.    -   Biofilm formation        shield against the patient's immune    -   system        use of antibiotics necessary.    -   Antibiotic resistant strains are spreading (actual rate of MRSE        related to all Staphylococcus epidermidis strains in Germany:        ca. 70%.). No relevant standard has been found in common        literature to assess the inhibition of a biofilm formation.        Consequently a custom-made test was developed: The tests were        performed using the Staphylococcus epidermidis ATCC 35984        strains. Pure silver rods were used as positive control and pure        titanium alloy rods were used as negative control.

FIG. 5 a illustrates the steps to prepare the samples and FIG. 5 b showsthe results of said biofilm formation test: The Bacteria amount found onthe nanoSilver, Ag-rods and Ti-alloy rods depending on the incubationtime. A sharp reduction of the bacteria amount has been observed on theAg—TiO₂ coating compare to titanium-alloy (>log 3 reduction) after 12 hof incubation. The nanoSilver coating even shows better results thanpure silver (FIG. 5 b). After 18 h of incubation, no more bacteria werefound on the surface of the Ag—TiO₂ coating. One explanation bases on anenhanced ratio of surface/volume of a nano-silver coating.

There exist several standard-test methods to determine the antimicrobialactivity of coated surfaces. For screening purposes, a proliferationtest is used. Bacteria commonly attend to adhere on surfaces. Thisambition is mainly disturbed by antimicrobial and/or hydrophobicfunctionalization of surfaces, leading to a strong decrease in bacteriaadhesion. The proliferation test shows this effect by the help of aspecific test procedure. The bacterial growth behavior leads to anestimation of an antimicrobial effect on treated surfaces compared to anuntreated surface. FIG. 6 a shows the steps to perform the proliferationtest.

The test is conducted with exponentially growing bacteria withcommercially available 96-well-microtiter-plate. The test specimensideally have a cylindrical shape with 4 mm diameter and a length of 12mm.

The bacterial proliferation is determined by measuring the opticaldensity at 578 nm in a special designed 64-fold-photometer.

For each sample an individual growth curve is displayed (see FIG. 6 e).The interpretation of the growth curves is illustrated in FIGS. 6 b to 6d: (b) exponential growth—no antibacterial activity, (c) lag phasegrowth—slight antibacterial activity and (d) no detectable growth—strongantibacterial activity.

Samples (in each test round, internal controls were also tested):

-   -   Negative control: HDPE-rods (have to show exponential growth).    -   Medium growth control: Some wells of the microtiter-plate were        filled up with contaminated nutrient solution to control the        bacterial growth under optimal conditions.    -   Sterility control: blank wells and uncontaminated samples shall        not show any bacterial growth.    -   Positive control: Pure Ag-rods (no growth should be detectable).

The antibacterial efficacy of the nanoSilver coating is estimated bycomparing the bacterial growth on that surface with an untreated surface(Blank).

-   -   Blank samples: TiAl6V4 Eli Alloy rods.    -   Samples with nanoSilver coating: TiAl6V4 Eli Alloy rods with        Ag—TiO₂ coating (5% recipe).

The results are presented in FIG. 6 e. All controls show the expectedgrowth curves, the test is valid. Compared to pure titanium rods, theAg—TiO₂ coated rods show a strong antibacterial efficacy, which is ashigh as of pure silver rods.

A test for antimicrobial activity and efficacy is performed according toJIS 22801. The JIS Z 2801 standard specifies the testing methods toevaluate antimicrobial activity and antimicrobial efficacy on bacteriaon the surface of antimicrobial products. The value of antimicrobialactivity shows the difference in the logarithmic value of viable cellcounts between antimicrobial products and untreated products afterinoculation and incubation of bacteria. So in contrast to theProliferation test the antibacterial activity can be quantified.

This testing method is applicable to products other than textileproducts, such as plastic products, metal products, and ceramicproducts.

The test samples were inoculated with a certain number of bacteria afterpreparation. To assure a good distribution of the inoculum, the testpiece is covered with a special film (PE-foil). The test pieces areincubated at 37° C. for 18 h. After incubation, the bacteria were washedout with nutrient solution. With this washing suspension a viable cellcount (agar plate culture method) is conducted.

Samples:

-   -   Blank sample: TiAl6V4 Eli Alloy disks.    -   Sample with nanoSilver coating: TiAl6V4 Eli Alloy disks with        Ag—TiO₂ coating (5% recipe).    -   Negative control: Polystyrene-surface (a certain number of        bacteria have to survive, otherwise the test has to be        rejected).

The results show a strong antimicrobial activity of the nanoSilver, withmore than log 4 reduction compared to TiAl6V4 Eli Alloy.

Further investigations were directed to silver leaching (according toISO 10993-17:2002). The intention of this work package includes thecorrelation between antimicrobial activity and amount of released silverions from the sample surface. It is developed a method of silver traceand species analysis with an appropriate method of sample preparation.The analysis is performed by graphite furnace atomic absorptionspectrometry (GF-AAS). The main focus has been laid on silver releasemechanisms under physiological conditions. A test set up has to becreated, which simulates conditions similar to the environment of thecoating in a patients tissue. Therefore Phosphate Buffered Saline (PBS)was chosen as a leaching agent.

The test procedure is as following:

Test series A (pseudo-dynamic model):

-   -   Samples are immersed in 1 ml PBS.    -   After 1 day gently shaking at 20° C. samples are transferred        into the next vial with new PBS.

Test series B (static model):

-   -   Samples are immersed in 10 ml PBS.    -   After certain intervals of gently shaking at 37° C. an aliquot        (0.5 ml) is transferred into a fresh vial.

The following test steps are analogue in both test series:

-   -   Ag content in PBS is analyzed after addition of nitric acid.    -   Silver analysis, done by graphite furnace atomic absorption        spectrometry (GF-AAS).

Tested samples:

-   -   Blank samples: TiAl6V4 Eli Alloy rods (Ti rod).    -   Samples with nanoSilver coating: TiAl6V4 Eli Alloy rods with        Ag—TiO₂ coating.    -   Positive control: pure silver rods (Ag rod)

The following results are achieved:

Test series A: The nanoSilver coating shows silver release quite similarto pure silver rods.

FIG. 7 shows analytical results obtained by GF-AAS of released Ag amount(ng) from the sample surface (mm²) as a function of immersion time(days) at RT in PBS. The displayed error bars show the variance of threeindependent analyses. The leaching rate is essentially uniform as afunction of immersion time.

After 15 days:

-   -   Daily release from pure silver rod remains constant after a        decrease in the first days.    -   Daily release from nanoSilver rod constant.    -   Sum of leached Ag amounts during 15 days of leaching: 6.3 μg.

The antibacterial activity (shown in the proliferation test) correspondsto the amount of released silver ions.

Test series B: According to our kinetics-test-conditions an equilibriumis reached after 24 hours.

     ??[?(?)] ?indicates text missing or illegible when filed

-   -   In this case the silver release at the equilibrium is about 0.4        ng·⁻¹·mm⁻²    -   If the 10 ml solution would be changed daily for 8 weeks, one        can expect a total silver release of about 22.4 ng·⁻¹·mm⁻².

FIG. 8 shows GF-AAS results of released Ag (ng) from the sample surface(mm²) as a function of time (days) at 37° C. in PBS. The analytical dataare a mean value of three independent analyses. The leaching rate isessentially uniform or constant as a function of immersion time.

FIGS. 9 a and 9 b show the results of a mechanical testing. Stereo lightmicroscopy images of a coated rod after bending test are presented. TheAg—TiO₂ coating adhesion has been investigated according to the ASTMB571-97 standard. The coated samples have been bent at various anglesand the deformed area has been observed by stereo light microscopy forany sign of peeling or flaking of the coating from the substrate. Nopeeling or flaking of the coating has been observed even after failureof the substrate has occurred. The adhesion strength of the coating isgreater than the cohesion strength of the substrate, which reveals aperfect adhesion according to the used standard.

FIG. 10 shows the experimental results with respect to biocompatibilityevaluation: ZK20 cells growing on nanoSilver/TiAl6V4 disks.

Cell culture has been performed using coated and uncoated TiAl6V4 disksas substrates. For this study two cell lines have been selected: theOsteosarcoma cell line (HOS TE85) and a primary mesenchymal stem cellsfrom human bone dust (ZK20). The samples incubation has been performedat 37° C. in a 95% air-5% CO₂ atmosphere. After various incubation times(days or weeks, depending on the cell lines) the samples were preparedfor light microscopy analysis and cells viability and proliferation havebeen investigated.

The two types of cell present a good adhesion and proliferation on thetwo types of surfaces (TiAl6V4 and nanoSilver). The two types of celltend to agglomerate on the nanoSilver coating surface.

After a special fixation procedure, aimed at killing the cells with theleast distortion of structure possible, the samples have been analyzedby electron microscopy. An SEM image of ZK20 cells on nanoSilver coatingis presented. The SEM image confirms the good cell adhesion andproliferation on the nanoSilver coating surface. Even a kind of cellanchor is visible.

Summarizing, it was shown that an Ag—TiO₂ coating according to theinvention shows excellent properties in terms of antibacterial efficacy(even against multi-resistant strains), adhesion and biocompatibility.

Finally, FIG. 11 presents a XRD image of a Ti-screw with a HA coating(hydroxyapatite). In detail it is presented the detected number ofcounts as a function of the angle 2 theta.

The parameters for this analysis are as follows:

-   -   Apparatus: Bruker D8 GADDS XRD (voltage: 40 KV and intensity: 40        mA)    -   Measurement range: Theta angle: 17-93.7° increment: 0.02° and        steptime: 60 s    -   Measuring point: Top of the titanium screw.

The sample contains mostly Titanium and Anatase (TiO₂). Titanium andTiO₂ originate from the bulk respectively the converted surface. Also avery small quantity of HA is detected. The intensity differences ofcertain HA peak is due to a preferential orientation of the crystalliteson the surface of the screw. However, these are the first hints that itis possible to detect HA itself on the converted surface and not onlyconstituents of HA.

The small amount of detected HA can be explained by the selectedconfiguration of the experimental set-up. The chosen angular range ofthe analysis beam results in an enhanced sensitivity to the bulkmaterial (Ti) covered with a layer of TiO₂ (thickness of several μm) andto a reduced sensitivity to a surface and a near surface composition ofHA (thickness of some 100 nm or below).

It is expected to detect an increasing amount of HA in a so-calledgrazing incidence geometry. In this geometry the analysis beam isdirected to the surface in a small angle (for instance of about 1.5degree) with respect to the surface which is to be analyzed. Thesensitivity for the surface composition and the near surface compositionis enhanced in this grazing incidence geometry.

It will be understood that the invention may be embodied in otherspecific forms without departing from the spirit or centralcharacteristics thereof. The present examples and embodiments,therefore, are to be considered in all respects as illustrative and notrestrictive, and the invention is not to be limited to the details givenherein. Accordingly, features of the above described specificembodiments can be combined with one another. Further, featuresdescribed in the summary of the invention can be combined with oneanother. Furthermore, features of the above described specificembodiments and features described in the summary of the invention canbe combined with one another

What is claimed is:
 1. A method for treating a surface of a medicaldevice, the method comprising: providing a colloid-dispersed system;subjecting a medical device to the colloid-dispersed system such that asurface of the medical device which is to be treated is immersed in thecolloid-dispersed system; and generating an AC voltage differencebetween i) the medical device as a first electrode and ii) a secondelectrode positioned in the colloid-dispersed system, in order toconvert the immersed surface to an oxide film by plasma electrolyticoxidation wherein the converted surface is partially covered by islandsformed by colloid-dispersed particles of the colloid-dispersed system.2. The method according to claim 1, wherein the maximum of the ACvoltage difference is provided in the range of 0.1 V to 4800 V.
 3. Themethod according to claim 1, wherein the AC voltage is provided as anasymmetric AC voltage.
 4. The method according to claim 3, wherein anegative component of the AC voltage is provided with an amplituderanging from −1200 V to −0.1 V and/or a positive component of the ACvoltage is provided with an amplitude ranging from 0.1 V to 4800 V. 5.The method according to claim 3, wherein the quotient of the positiveamplitude divided by the negative amplitude is adjusted to the absolutevalue of the quotient ranging from >1 to
 4. 6. The method according toclaim 1, wherein the AC voltage is provided as a symmetric AC voltage.7. The method according to claim 6, wherein a negative component of theAC voltage is provided with an amplitude ranging from −2400 V to −0.1 Vand/or a positive component of the AC voltage is provided with anamplitude ranging from +0.1 V to +2400 V.
 8. The method according toclaim 1 wherein the colloid-dispersed system is a water-baseddispersion.
 9. The method according to claim 1 wherein at least oneelectrolyte is provided in the colloid-dispersed system.
 10. The methodaccording to claim 1 wherein the colloid-dispersed particles areprovided by at least one member of a group consisting of Ag-particles,apatite-particles, Cu-particles, Zn-particles and a component which isat least one component of a material of the medical device.
 11. Themethod according to claim 1 wherein the colloid-dispersed particles areprovided as an additive wherein the additive is at least one materialselected from a group consisting of metals, oxides, earth minerals andphosphates.
 12. The method according to claim 1 wherein thecolloid-dispersed particles are provided with a concentration of lessthan or equal to 100 mg/l. 13-22. (canceled)
 23. A method for treating asurface of a medical device, the method comprising: providing acolloid-dispersed system; subjecting a medical device to thecolloid-dispersed system such that a surface of the medical device whichis to be treated is immersed in the colloid-dispersed system; andgenerating an AC voltage difference between i) the medical device as afirst electrode and ii) a second electrode positioned in thecolloid-dispersed system, in order to convert the immersed surface to anoxide film by plasma electrolytic oxidation wherein the convertedsurface is partially covered by islands formed by colloid-dispersedparticles of the colloid-dispersed system, wherein the AC voltage isprovided as an asymmetric AC voltage and/or as a sinus-shaped ACvoltage, and wherein the AC voltage difference is generated by a powersupply unit and supplied to the first electrode and/or the secondelectrode such that a uniform electric field distribution is achieved byproviding means for connecting the first electrode having an adaptedreduced or an adapted increased cross section with respect to the crosssection of the connected medical device.